tbuckley/cabot-search huggingface dataset:
Development and Validation of a Deep Learning Model to Predict the Occurrence and Severity of Retinopathy of Prematurity
Authors: Qiaowei Wu, Yijun Hu, Zhenyao Mo, Rong Wu, Xiayin Zhang, Yahan Yang, Baoyi Liu, Yu Xiao, Xiaomin Zeng, Zhanjie Lin, Ying Fang, Yijin Wang, Xiaohe Lu, Yanping Song, Wing W. Y. Ng, Songfu Feng, Honghua Yu
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Retinopathy of prematurity (ROP) is the leading cause of childhood blindness worldwide. Prediction of ROP before onset holds great promise for reducing the risk of blindness. <h3>Objective</h3> To develop and validate a deep learning (DL) system to predict the occurrence and severity of ROP before 45 weeks' postmenstrual age. <h3>Design, Setting, and Participants</h3> This retrospective prognostic study included 7033 retinal photographs of 725 infants in the training set and 763 retinal photographs of 90 infants in the external validation set, along with 46 characteristics for each infant. All images of both eyes from the same infant taken at the first screening were labeled according to the final diagnosis made between the first screening and 45 weeks' postmenstrual age. The DL system was developed using retinal photographs from the first ROP screening and clinical characteristics before or at the first screening in infants born between June 3, 2017, and August 28, 2019. <h3>Exposures</h3> Two models were specifically designed for predictions of the occurrence (occurrence network [OC-Net]) and severity (severity network [SE-Net]) of ROP. Five-fold cross-validation was applied for internal validation. <h3>Main Outcomes and Measures</h3> Area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity to evaluate the performance in ROP prediction. <h3>Results</h3> This study included 815 infants (450 [55.2%] boys) with mean birth weight of 1.91 kg (95% CI, 1.87-1.95 kg) and mean gestational age of 33.1 weeks (95% CI, 32.9-33.3 weeks). In internal validation, mean AUC, accuracy, sensitivity, and specificity were 0.90 (95% CI, 0.88-0.92), 52.8% (95% CI, 49.2%-56.4%), 100% (95% CI, 97.4%-100%), and 37.8% (95% CI, 33.7%-42.1%), respectively, for OC-Net to predict ROP occurrence and 0.87 (95% CI, 0.82-0.91), 68.0% (95% CI, 61.2%-74.8%), 100% (95% CI, 93.2%-100%), and 46.6% (95% CI, 37.3%-56.0%), respectively, for SE-Net to predict severe ROP. In external validation, the AUC, accuracy, sensitivity, and specificity were 0.94, 33.3%, 100%, and 7.5%, respectively, for OC-Net, and 0.88, 56.0%, 100%, and 35.3%, respectively, for SE-Net. <h3>Conclusions and Relevance</h3> In this study, the DL system achieved promising accuracy in ROP prediction. This DL system is potentially useful in identifying infants with high risk of developing ROP.
Abstract 172: Limiting medulloblastoma progression by hindering the Hedgehog signaling pathway with novel atypical protein kinase C inhibitors
Authors: Luke Lajmi, Sloan Breedy, Wishrawana S. Ratnayake, Mildred Acevedo-Duncan
Journal: Cancer Research (2022)

Abstract Medulloblastoma is the most common pediatric brain tumor, constituting 20% of all childhood brain cancers (Clin. Cancer Res. 2008, 14 (4), 971-976., Oncogenesis 2019, 8 (11), 1-11). It is a highly invasive tumor that originates in the cerebellum and has the ability to metastasize throughout the central nervous system early in its course. The median age of diagnosis is 5 years, with 80% of cases being diagnosed in the first 15 years (Asian J. Neurosurg. 2015, 10 (1), 1-4). Current treatment options include maximal safe resection, chemotherapy and craniospinal radiation (J. Neurosurg. Pediatr. 2019, 24(4), 353-363). Despite such aggressive therapeutic treatments, nearly 30% of afflicted patients succumb to this disease, and survivors cope with the long-term side effects of these treatments that have significant impacts on their quality of life (J. Neurosurg. Pediatr. 2019, 24(4), 353-363). This underscores the need for less invasive and more effective treatment methods to improve overall patient outcomes. We believe that oncogene expression resulting from the Hedgehog (Hh) signaling pathway is responsible for upregulating malignant cancer cell growth, cell survival, and migration. Preliminary dose curve studies, in which D341 and D283 medulloblastoma cell lines were treated with novel atypical protein kinase C (aPKC) inhibitors 2-acetyl-1,3-cyclopentanedione (ACPD) and 3,4-diaminonapthalene-2,7-disulfonic acid (DNDA) (Int. J. Oncol. 2017, 51(5), 1370-1382), have been shown to significantly decrease cell proliferation with increasing inhibitor concentration. Cell line D341 showed 44.2% inhibition when treated with 10 µM of ACPD and 75.2% inhibition when treated with 1 µM of DNDA while cell line D283 showed a 63.2% inhibition at 5 µM of ACPD and 73.6% inhibition at 10 µM. Future studies will be conducted to determine the inhibition mechanism of the Hh pathway in medulloblastoma by probing for different cell cycle and oncoprotein markers using Western blotting, employing the WST-1 assay to evaluate cell viability and cytotoxicity, and implementing migration and invasion assays. Citation Format: Luke Lajmi, Sloan Breedy, Wishrawana S. Ratnayake, Mildred Acevedo-Duncan. Limiting medulloblastoma progression by hindering the Hedgehog signaling pathway with novel atypical protein kinase C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 172.
Abstract 1636: A new invasive zebrafish model of Ewing sarcoma reveals EWSR1-FLI1-driven dysregulation of heparan sulfate proteoglycan metabolism in developing tumors
Authors: Elena Vasileva, Mikako Warren, Timothy Triche, James Amatruda
Journal: Cancer Research (2022)

Abstract Ewing sarcoma (ES) is a malignant bone and soft-tissue tumor with an extremely poor prognosis for patients with metastatic or relapsed disease. ES is characterized by the appearance of a chimeric fusion oncogene, most frequently EWSR1-FLI1 (EF1). In the absence of a representative in vivo model the role of tumor cell/microenvironmental interactions in tumor initiation and progression remains a subject of constant debate. To address these concerns, we developed an innovative Cre-inducible model of ES in zebrafish which allows broad mosaic expression of human EF1 in zebrafish, which causes rapid onset of ES at high penetrance. This invasive model allows study of the behavior of GFP-labeled cancer cells during tumor initiation and progression, in a complex developmental context which is not currently possible in mammals. We found that observed tumors express canonical EF1 target genes and stain for known ES markers including CD99. Proteomic analysis revealed that EF1 expression affects heparan sulfate proteoglycan (HSPG) metabolism and activates HSPG-mediated ERK signaling in EF1 expressing cells, promoting cancer cell survival and proliferation. Proteoglycans are key regulators of signaling of cell surface receptors, playing an essential role in cell-to-cell communication. Targeting heparan sulfate proteoglycans with the specific heparan sulfate antagonist Surfen reduces ERK1/2 signaling and decreases tumorigenicity of ES cells in vitro and in vivo. These results highlight the important role of the extracellular matrix in ES tumor growth and the potential of agents targeting proteoglycan metabolism as novel therapies for this disease. Citation Format: Elena Vasileva, Mikako Warren, Timothy Triche, James Amatruda. A new invasive zebrafish model of Ewing sarcoma reveals EWSR1-FLI1-driven dysregulation of heparan sulfate proteoglycan metabolism in developing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1636.
Abstract 3245: Genes associated with Src-Met driven resistance of head &amp; neck cancers to EGFR-PI3K cotargeting
Authors: Adeoluwa A. Adeluola, A.R.M. Ruhul Amin
Journal: Cancer Research (2022)

Abstract Background: In recent years, oncology research has led to the discovery of targeted therapies aimed at specific genetic abnormalities unique to cancer cells. In particular, the overexpression of epidermal growth factor receptor (EGFR) and constitutive activation of the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) pathway are common aberrations in head and neck cancer. However, intrinsic and acquired resistance are continuously posing challenges to success. Previously, we reported that the combination of EGFR inhibitor erlotinib with PI3K inhibitor BKM120 had synergistic effects that induced efficient apoptosis in a panel of head and neck cancer cell lines, but some cells were still resistant. The purpose of the current study is to understand the mechanism of resistance to EGFR and PI3-K co-targeting. Hypothesis: Src-Met signaling confers apoptosis resistance to EGFR and PI3K cotargeting by regulating downstream genes expresiion. Methods: Apoptosis was measured by annexin V-PE staining. Western blotting and qPCR were used for measuring the expression of proteins and mRNA, respectively. RNASeq was conducted from RNA samples treated with (Erlotinib + BKM120) ± dasatinib (Src inhibitor)/crizotinib(Met inhibitor). Results: Biochemical studies revealed that JHU022 cells, which were resistant to the combination treatment, had an overactivation of c-Met receptor tyrosine kinase that was regulated by Src kinases. Pharmacological or genetic inactivation of both Met or Src kinase sensitized this cell line to apoptosis induced by EGFR and PI3K co-targeting. RNA-Seq analysis identified that a total of 291 genes were modulated (2-folds) by both crizotinib and dasatinib. Pathway enrichment suggested that many of these genes were associated with cell cycle, DNA replication, and cellular response to DNA damage. CPA4 was identified as the most downregulated gene and GDF15 as one of the top upregulated genes. Conclusions: SRC-Met signaling confers resistant to EGFR and PI3K cotargeting by modulating genes associated with cell cycle, DNA replication, and cellular response to DNA damage. Citation Format: Adeoluwa A. Adeluola, A.R.M. Ruhul Amin. Genes associated with Src-Met driven resistance of head &amp; neck cancers to EGFR-PI3K cotargeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3245.
Abstract 6269: A cell double barcoding system for quantitative evaluation of primary tumors &amp; metastasis in animals: Uncovers clonal-specific anti-cancer drug effects
Authors: Arkadi Hesin, Santosh Kumar, Valid Gahramanov, Maria Becker, Maria Vilenchik, Ilya Alexandrov, Julia Yaglom, Michael Sherman
Journal: Cancer Research (2022)

Abstract Imaging in monitoring metastasis in mouse models have low sensitivity and is not quantitative. Cell DNA barcoding, demonstrating high sensitivity and resolution, allows monitoring effects of drugs on the number of tumor and metastatic clones. However, this technology is not suitable for comparison of sizes of metastatic clones in different animals, e.g. drug treated and untreated, due to high biological and technical variability upon tumor and metastatic growth and isolation of barcodes from tissue DNA. Yet, both numbers of clones and their sizes are critical parameters for analysis of drug effects. Here we developed a modification of the barcoding approach for monitoring drug effects on tumors and metastasis that is quantitative, highly sensitive and highly reproducible. This novel cell double barcoding system allows simultaneously following the fate of two or more cell variants or cell lines in xenograph models in vivo, and also following the fates of individual clones within each of these populations. This system allows comparing effects of drugs on different cell populations, and thus normalizing drug effects by drug-resistant lines, which corrects for both biological and technical variabilities and significantly increases the reproducibility of results. Using this barcoding system, we uncovered that effects of a novel DYRK1B kinase inhibitor FX9847 on primary tumors and metastasis is clone-dependent, while a distinct drug osimertinib demonstrated clone-independent effects on cancer cell populations. Overall cell double barcoding approach can significantly enrich our understanding of drug effects in basic research and preclinical studies. Citation Format: Arkadi Hesin, Santosh Kumar, Valid Gahramanov, Maria Becker, Maria Vilenchik, Ilya Alexandrov, Julia Yaglom, Michael Sherman. A cell double barcoding system for quantitative evaluation of primary tumors &amp; metastasis in animals: Uncovers clonal-specific anti-cancer drug effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6269.
Abstract 3869: A human <i>in-vitro</i> T cell exhaustion model for assessing immuno-oncology therapies
Authors: Paulina Goral, Louise Brackenbury, Robert Nunan, Rhiannon Jenkinson
Journal: Cancer Research (2022)

Abstract Chronic stimulation of CD8 T cells either as a result of viral infection or within the tumor microenvironment can lead to a state of exhaustion, whereby T cells no longer make a productive effector response. Remobilisation of exhausted tumor specific CD8 T cells (TEX) presents a possible therapeutic strategy for driving anti-tumor T cell responses. The success of biologics targeting receptors and ligands associated with exhausted T cells such as PD-1/PD-L1 and CTLA-4 has spurred an acceleration of research to unravel the molecular processes that drive or maintain the exhausted state with the goal of developing treatments that target them. Effective therapeutic development necessitates reliable human in-vitro models that closely mimic disease conditions. To achieve this we adapted an in-vitro TEX model via application of flowing cytometry and time-lapse imaging techniques to kinetically assess TEX cell phenotype and function. Persistent and repeated rounds of polyclonal human CD8 T cell stimulation recapitulated distinctive characteristics of exhausted T cells including high expression of checkpoint receptors and upregulation of transcription factors known to suppress immune activation. Over 8 days and 4 rounds of stimulation TEX cells lost effector capabilities, producing lower levels of pro-inflammatory cytokines and became refractory to re-stimulation through the TCR. In functional cytotoxicity assays TEX cells exhibited substantial deficits in target killing compared to donor matched Teff cell counterparts. Checkpoint receptor blockade partially restored Teff function by enhancing immune mediated target cell death. Overall, this in-vitro TEX assay models key aspects of CD8 T cell exhaustion and offers a versatile and accessible platform to test novel therapeutics targeting exhaustion pathways either individually or in combination with checkpoint inhibitors to test if they fully restore effector function. Citation Format: Paulina Goral, Louise Brackenbury, Robert Nunan, Rhiannon Jenkinson. A human in-vitro T cell exhaustion model for assessing immuno-oncology therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3869.
Abstract 1423: NKX3.1 expression predicts response to metformin intervention in prostate cancer
Authors: Alexandros Papachristodoulou, Aditya Dutta, Cory Abate-Shen
Journal: Cancer Research (2022)

Abstract The goal of precision prevention is to tailor interventions based on individualized patient cancer risk and likelihood of progression. This approach is particularly relevant for prostate cancer since it is characteristically indolent, and thus delaying disease progression can be highly advantageous for patients. Therefore, identifying molecular features predictive of cancer progression and response to specific interventions is vital to improve precision prevention in prostate cancer. In this regard, expression levels and localization of the tissue-specific homeobox protein, NKX3.1, helps distinguish men with high risk for developing more aggressive prostate cancer. Our recent study revealed a novel function for NKX3.1 in mitochondria, where it regulates aberrant mitochondrial oxidative stress to suppress prostate cancer initiation. Lower NKX3.1 expression levels at gene and protein levels are associated with poor outcome and higher risk for aggressive prostate cancer. We are now investigating the role of NKX3.1 as a prognostic marker and potential target for prostate cancer precision prevention interventions. Our new preliminary data indicate a role for metformin as a preventative intervention in contexts of reduced NKX3.1. Specifically, we have shown that metformin reduces oxidative stress and suppresses cancer initiation in the prostates of Nkx3.1 mutant mice. Moreover, studies in human prostate cancer cells as well as human prostate cancer organotypic assays revealed that metformin can indeed, restore mitochondrial function and inhibit tumorigenicity in the absence of NKX3.1. Although men on active surveillance for prostate cancer may benefit from metformin intervention, it has been unclear whether metformin is effective in delaying disease progression and, if so, whether specific patients are more likely to benefit. Our new data implicate NKX3.1 status as a predictor of response to metformin, suggesting that it can stratify high-risk prostate cancer patients most likely to benefit from such intervention during active surveillance. Citation Format: Alexandros Papachristodoulou, Aditya Dutta, Cory Abate-Shen. NKX3.1 expression predicts response to metformin intervention in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1423.
Abstract 1689: Heterogeneity of tumor-initiating cell related signaling revealed by lentiviral signaling reporters in breast cancer patient-derived xenografts
Authors: John Landua, Ping Gong, Michael T. Lewis
Journal: Cancer Research (2022)

Abstract Classical markers of tumor-initiating cells (TIC), aldehyde dehydrogenase 1 (ALDH1) activity and the cell-surface markers, CD44pos/CD24low/neg, show insufficient cell type specificity to identify TIC definitively, nor do they allow robust enrichment by FACS. As a consequence, analyses of TIC function and gene expression to date are not definitive. Identification and characterization of the TIC subpopulation is critically important in breast cancer since these cells are thought to mediate treatment resistance, as well as local and distant recurrence. This is particularly critical for “triple negative” breast cancer (TNBC), since currently there are no targeted therapies available for this clinical subtype. Lentiviral signaling reporter vectors allow purification of enriched TIC subpopulations thereby facilitating single cell analyses to identify distinct sets of cells with TIC features. We used a collection of fluorescent lentiviral reporters that enable visualization and flow cytometric enrichment of cells undergoing STAT3-, GLI-, WNT-, or OCT4/SOX2-mediated transcriptional activity. Our collection of patient derived xenograft (PDX) models of TNBC were infected with the lentiviral reporters, re-transplanted, and screened for reporter activity upon regrowth. TIC function of reporter-expressing cells relative to negative cells was assayed by mammosphere formation and limiting dilution transplantation. Reporter expressing cells with enriched TIC function were then analyzed by single cell RNAseq for expression of classical markers to identify the subset of cells most likely to represent the TIC subpopulation. Our results indicate that STAT3 and GLI transcriptional activity can serve as uniquely PDX-dependent indicators for TIC function for a subpopulation of cancer cells. Also, multiple potential TIC signaling pathways, including STAT3, GLI, WNT, and OCT4/SOX2, can be active in a single PDX model, but do not necessarily associate with TIC function, indicating TIC diversity in TNBC. These data in conjunction with treatment response and single-cell RNA-seq sheds light on the molecular diversity of TIC populations in TNBC, identifies candidate targets for therapeutic intervention, and will indicate whether TIC diversity is associated with differential response to different chemotherapeutic agents. Citation Format: John Landua, Ping Gong, Michael T. Lewis. Heterogeneity of tumor-initiating cell related signaling revealed by lentiviral signaling reporters in breast cancer patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1689.
Abstract 1332: Adar1 impacts pancreatic homeostasis and pancreatic tumor biology
Authors: Dhwani Rupani, Robert Cowan, Chris Gates, Florencia McAllister, Andrew Rhim
Journal: Cancer Research (2022)

Abstract Adenosine-to-Inosine (A-to-I) RNA editing is mediated by Adenosine deaminase acting on RNA (Adar) enzymes. The resulting A-to-I edit in RNA alters its post-transcriptional processing making Adar1 a critical regulator of gene expression. In line with its role in gene regulation, Adar1 has been implicated in development and organogenesis. We investigated the role of Adar1 in pancreatic development and homeostasis, and observed that though Adar1 is not required for pancreatic development, it is essential for pancreatic homeostasis. We observed that loss of Adar1 can stimulate a Mavs-mediated innate immune pathway and results in influx of immune cells in the pancreas. Pancreatic tumors are notorious for their immunosuppressive microenvironment. Since loss of Adar1 can activate a Mavs-mediated innate immune pathway, we next investigated the role of ADAR1 in human pancreatic ductal adenocarcinoma cell lines. We developed a bioinformatics pipeline, Cancer RSNV (RNA Single Nucleotide Variant) Identifier and Annotator (CRIDA) to identify A-to-I RNA edits in pancreatic cancer and observed wide-spread ADAR1-mediated RNA editing in pancreatic cancer cells. We analyzed genes that are differentially regulated between ADAR1 knockdown and control cells, and observed a differential immune signaling. Together, our data suggests that Adar1 is important for pancreatic homeostasis and tumor biology. Citation Format: Dhwani Rupani, Robert Cowan, Chris Gates, Florencia McAllister, Andrew Rhim. Adar1 impacts pancreatic homeostasis and pancreatic tumor biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1332.